Aeromagnetic lineaments interpreted from reduced-to-pole (RTP) magnetic grids were compared with gravity, topography, and field-based geologic maps to infer regional structural controls on hydrothermal mineral occurrences in a poorly exposed portion of the North American Cordillera in western Yukon and eastern Alaska. High-frequency and variable-intensity aeromagnetic lineaments corresponding to discontinuities with an aeromagnetic domain change were interpreted as steep-dipping and either magnetite-destructive or magnetite-additive faults. These structures were interpreted to be predominantly Cretaceous in age and to have formed after the collision of the Intermontane terranes with the ancient Pacific margin of North America. To demonstrate the reliability of the aeromagnetic interpretation, we developed a multidata set stacking methodology that assigns numeric values to individual lineaments depending on whether they can be traced in residuals and first vertical derivative of RTP aeromagnetic grids, isostatic residual gravity grids, digital topography, and regional geologic maps. The sum of all numeric values was used to estimate the likelihood of the aeromagnetic lineament as a true geologic fault. Fault systems were interpreted from zones of lineaments with high spatial density. Using this procedure, 10 major northwest-trending fault systems were recognized. These were oriented subparallel to the regional Cordilleran deformation fabric, the mid-Cretaceous Dawson Range magmatic arc, and well-established crustal-scale dextral strike-slip fault systems in the area. These orogen-parallel fault systems were interpreted to play a structural role in the emplacement of known porphyry Cu-Au and epithermal Au systems of mid-Cretaceous (115–98 Ma) and Late Cretaceous (79–72 Ma) age. The procedure also identified seven northeast-trending, orogen-perpendicular fault-fracture systems that are prominent in eastern Alaska and exhibit sinistral-to-oblique extensional kinematics. These structures were interpreted to govern the emplacement of Late Cretaceous (72–67 Ma) porphyry Mo- and Ag-rich polymetallic vein and carbonate replacement systems in the region.